JPH07252155A - Prostacyclin-containing percutaneous composition - Google Patents

Abstract

PURPOSE:To obtain a percutaneous composition containing a prostacyclin and excellent in percutaneous absorption and durability of drug efficacy by using a specified base and a specified solubilizing agent in combination. CONSTITUTION:This percutaneous composition contains a compound of the formula [R<1> is H or a 1 to 10C alkyl; R<2> is R<21> or (CH2)nR<22>; R<21> is a 3 to 12C alkyl, an alkenyl or an alkynyl; R<22> is a 3 to 10C cycloalkyl; (n) is 0 to 2; R<3> and R<4> are H, C(=O)R<5>; R<5> is a 1 to 5C alkyll and/or its enantiomer in an amount of 0.000001 to 0.1wt.%. As the dosage form, fatty ointment is preferable and preparation is carried out by using a higher paraffinic hydrocarbon (e.g. a mixture of paraffin and white vaseline) as the base and a fatty acid ester (e.g. diisopropyl adipate) as the solubilizing agent. This medicine is excellent in, e.g. durability of drug efficacy, stability of the active component and low stimulation to the skin and useful as a medicine for therapy of ulcerative dermatosis and peripheral circulatory disorder such as Buerger disease.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation containing prostacyclins as an active ingredient and having an excellent duration of drug effect, particularly to an oily ointment.

[0002]

2. Description of the Related Art Antibacterial agents for the purpose of sterilization as therapeutic agents for various skin ulcers such as pressure ulcers and burns, enzyme preparations for the purpose of digesting tissues, skin wipes or water-absorbing polymer powders, and wound dressings. Etc. are used. In recent years, as a drug having a new mechanism of action, attempts have been made to apply prostaglandins having a peripheral circulation improving action, a platelet aggregation inhibiting action or a vasodilating action as a percutaneous absorption type formulation to these skin ulcers ( JP-A-63-99866, JP-A-63-135333, JP-A-63-1468
No. 12, JP-A-1-143340, JP-A-3
-83925, JP-A-3-83926, JP-A-4-164034, and JP-A-4-243827.
JP-A-4-243827, JP-A-4-3827
Gazette).

Preparations for dermal application include semi-solid preparations (ointments, creams), patches, lotions, etc., but are applied to a skin ulcer site due to peripheral circulatory failure or a site that may become a skin ulcer. With regard to (1), an ointment having less irritation, particularly an oily ointment, is preferred. The following prior arts have been reported with regard to oil-and-fat ointments of prostaglandins (JP-A-4-243827).

[0004]

The use of the compound of the above formula [1] and its isomer as an external preparation suggests its potential as a therapeutic agent for peripheral circulatory insufficiency such as ulcerative skin disease and Buerger's disease. A pharmacological activity was obtained. In the case of skin diseases with ulcers, the skin is not keratinous, and therefore, when the external preparation is applied, the main drug generally easily penetrates the skin. On the other hand, in peripheral circulatory insufficiency, when there is no ulcer in Raynaud's disease or Burger's disease, keratin is present on the skin at the drug administration site and absorption is poor. By the way, prostaglandins are generally extremely active and have a short life span in vivo. Therefore, when designing an external preparation containing prostaglandins as the main drug, it is not enough to simply increase the transdermal absorption amount, and constant release of the main drug from the base is extremely important in preventing side effects. is important. If such controlled release is possible, the concentration of the main drug in the base can be lowered, which is useful from the viewpoint of safety and economy. In an ointment prepared by the method for formulating a general oil-and-fat ointment disclosed in the prior art (JP-A-4-243827), a rapid release occurs shortly after application (burst phenomenon), and then release. The quantity decreases rapidly. Therefore, when these are applied to a site such as a skin ulcer without a barrier due to keratin, side effects specific to prostaglandins such as erythema and pain may occur. Therefore, the object of the present invention is to use prostacyclins as an external preparation, which can be safely used for skin diseases regardless of the presence of keratin, has excellent transdermal absorbability, and improves the release of the main drug from the base. To develop a specific formulation.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to solve the above problems, and as a result, selected a combination of a base and a solubilizing agent to obtain the prostas represented by the above formula [1]. The present invention has been accomplished by finding out an oily ointment having excellent transdermal absorbability of glandins and long-lasting drug effect.

That is, the present invention has the following formula [1] as a medicinal component.

[0007]

[Chemical 3]

[In the formula, R ¹ represents a hydrogen atom or a C ^{1 to} C ¹⁰ linear or branched alkyl group. R ² represents R ²¹ or (CH ₂ ) nR ²² , wherein R ²¹ represents an optionally substituted C _{3 to} C ₁₂ linear or branched alkyl group, alkenyl group or alkynyl group, R ²² represents an optionally substituted C ₃ -C ₁₀ cycloalkyl group, and n represents an integer of 0-2. R ³ and R ⁴ are each independently a hydrogen atom or the formula [2]

[0009]

[Image Omitted] -C (= O) R ⁵ --- [2]

(Wherein R ⁵ represents a C ₁ -C ₅ linear or branched alkyl group)] and / or its enantiomer, and a higher paraffin base as a base. It is intended to provide a prostacyclin-containing skin application composition comprising a hydrocarbon and a fatty acid ester as a solubilizing agent.

The present invention provides a prostacyclin-containing skin application composition in which the higher paraffinic hydrocarbon in the base is a mixture of paraffin and white petrolatum, and liquid paraffin is optionally added. included.

Furthermore, the present invention includes a prostacyclin-containing dermal application composition in which the fatty acid ester as a solubilizer is diisopropyl adipate.

In the above formula [1], R ₁ is a hydrogen atom,
It represents a C _{1 to} C ₁₀ linear or branched alkyl group. Examples of the C _{1 to} C ₁₀ alkyl group include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group,
n-butyl group, sec-butyl group tert-butyl group,
n-pentyl group, n-hexyl group, n-heptyl group, n
Examples thereof include -octyl group, n-nonyl group, and n-decyl group. Among them, C _{1 to} C ₆ alkyl groups,
Especially alkyl groups of C ₁ -C ₄ are preferred. R ₁ is particularly preferably a hydrogen atom or a methyl group, and particularly preferably a methyl group.

In the above formula [1], R ² represents R ²¹ or (CH ₂ ) _n R ²² . Here, R ²¹ is an optionally substituted C _{3 to} C ₁₂ linear or branched alkyl group,
It represents an alkenyl group or an alkynyl group, R ²² represents an optionally substituted C ₃ -C ₁₀ cycloalkyl group, and n represents an integer of 0-2. Unsubstituted C for R ²¹
Examples of the alkyl group of _{3 to} C ₁₂ include n-propyl group, n-butyl group, n-pentyl group, 3-methylbutyl group, n-hexyl group, 4-methylpentyl group, 3,3-dimethylbutyl group, n-heptyl group, 5 -Methylhexyl group, 4-methylhexyl group, 3-methylhexyl group,
n-octyl group, 6-methylheptyl group, 5-methylheptyl group, 4-methylheptyl group, 3-methylheptyl group, n-nonyl group, 7-methyloctyl group, 6-methyloctyl group, 5-methyloctyl group, 4-methyloctyl group, 3-methyloctyl group, iso-propyl group, Two
-Methylbutyl group, 2-methylpentyl group, 2,3-dimethylbutyl group, 2-methylhexyl group, 2,4-dimethylpentyl group, 2,2,3-trimethylbutyl group, 2
-Methylheptyl group, 2,5-dimethylhexyl group,
2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2-methyloctyl group, 2,6-dimethylheptyl group, 2,5-dimethylheptyl group, 2,4-dimethylheptyl group, 2,3-dimethylheptyl group Group, 2-methylnonyl group, 2,7-dimethyloctyl group, 2,6-dimethyloctyl group, 2,5-dimethyloctyl group, 2,4
Examples thereof include a dimethyl occlu group and a 2,3-dimethyl octyl group. Among these, C _{3 to} C ₁₀ alkyl groups, particularly C _{5 to} C ₁₀ alkyl groups are preferable.

Further, the unsubstituted C ₃ -C ₁₂ alkenyl group for R ²¹ is, for example, 3-butenyl group, 2-methyl-3-butenyl group, 3-pentenyl group, 2-methyl-3.
-Pentenyl group, 4-pentenyl group, 2-methyl-4-pentenyl group, 2,3-dimethyl-4-pentenyl group,
3-methyl-4-pentenyl group, 3-ethyl-2-methyl-4-pentenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-3-hexenyl group, 2-methyl-4-hexenyl group, 2-methyl-5
-Hexenyl group, 5-methyl-3-hexenyl group, 5,
5-dimethyl-hexenyl group, 2,5-dimethyl-3-hexenyl group, 2,3-dimethyl-4-hexenyl group,
4-methyl-5-hexenyl group, 2,4-dimethyl-5
-Hexenyl group, 4,4-dimethyl-5-hexenyl group, 2,4,4-trimethyl-5-hexenyl group, 3-methyl-5-hexenyl group, 2,3-dimethyl-5-hexenyl group, 3-heptenyl group, 4-heptenyl group, 5
-Heptenyl group, 6-heptenyl group, 2-methyl-3-heptenyl group, 2-methyl-4-heptenyl group, 2-methyl-5-heptenyl group, 2-methyl-6-heptenyl group, 5-methyl-6-heptenyl group, 2,5-dimethyl-6-heptenyl group, 5,5- Dimethyl-6-heptenyl group, 2,5,5-trimethyl-6-heptenyl group, 5
-Ethyl-6-pentenyl group, 5-ethyl-2-methyl-6-heptenyl group, 4-methyl-6-heptenyl group,
2,4-dimethyl-6-heptenyl group, 4,4-dimethyl-6-heptenyl group, 2,4,4-trimethyl-6-heptenyl group, 3-methyl-6-heptenyl group, 2,3
-Dimethyl-6-heptenyl group, 6-methyl-4-heptenyl group, 2,6-dimethyl-4-heptenyl group, 6,
6-dimethyl-4-heptenyl group, 2,6,6-trimethyl-4-heptenyl group, 3-methyl-5-heptenyl group, 2,3-dimethyl-5-heptenyl group, 3-methyl-4-heptenyl group, 5-methyl-3-heptenyl group,
2,5-dimethyl-3-heptenyl group, 3-octenyl group, 4-octenyl group, 5-octenyl group, 6-octenyl group, 7-octenyl group, 2-methyl-3-octenyl group, 2-methyl-4-octenyl group, 2-methyl-5
-Octenyl group, 2-methyl-6-octenyl group, 2-methyl-7-octenyl group, 6-methyl-7-octenyl group, 2,6-dimethyl-7-octenyl group, 6,6-
Dimethyl-7-octenyl group, 2,6,6-trimethyl-7-octenyl group, 5-methyl-7-octenyl group,
2,5-dimethyl-7-octenyl group, 4-methyl-7
-Octenyl group, 2,4-dimethyl-7-octenyl group, 4,4-dimethyl-7-octenyl group, 2,4,4
-Trimethyl-7-octenyl group, 3-methyl-7-octenyl group, 2,3-dimethyl-7-octenyl group,
3,3-Dimethyl-7-octenyl group, 2,3,3-trimethyl-7-octenyl group, 3-methyl-6-octenyl group, 2,3-dimethyl-6-octenyl group, 4-methyl-6-octenyl group, 2,4-dimethyl-6-octenyl group, 4 , 4-dimethyl-6-octenyl group, 2,
4,4-trimethyl-6-octenyl group, 5-methyl-6-octenyl group, 2,5-dimethyl-6-octenyl group, 5,5-dimethyl-6-octenyl group, 2,5,5
-Trimethyl-6-octenyl group, 7-methyl-5-octenyl group, 2,7-dimethyl-5-octenyl group, 4
-Methyl-5-octenyl group, 2,4-dimethyl-5-octenyl group, 4,4-dimethyl-5-octenyl group,
2,4,4-trimethyl-5-octenyl group, 7,7-
Dimethyl-5-octenyl group, 2,7,7-trimethyl-5-octenyl group, 6-methyl-4-octenyl group,
2,6-dimethyl-4-octenyl group, 6-ethyl-4
-Octenyl group, 6-ethyl-2-methyl-4-octenyl group, 6,6-dimethyl-4-octenyl group, 2,
6,6-trimethyl-4-octenyl group, 5-methyl-3-octenyl group, 2,5-dimethyl-3-octenyl group, 6-methyl-3-octenyl group, 2,6-dimethyl-3-octenyl group, 7-methyl-3-octenyl group,
2,7-Dimethyl-3-octenyl group, 3-nonenyl group, 4-nonenyl group, 5-nonenyl group, 6-nonenyl group, 7-nonenyl group, 8-nonenyl group, 2-methyl-3
Nonenyl group, 2-methyl-4-nonenyl group, 2-methyl-5-nonenyl group, 2-methyl-6-nonenyl group, 2-methyl-7-nonenyl group, 2-methyl-8-nonenyl group, 7-methyl-8-nonenyl group, 2,7-dimethyl-8-nonenyl group, 7, 7-dimethyl-8-nonenyl group,
2,7,7-Trimethyl-8-nonenyl group, 6-methyl-8-nonenyl group, 2,6-dimethyl-8-nonenyl group, 6,6-dimethyl-8-nonenyl group, 2,6,6-
Trimethyl-8-nonenyl group, 5-methyl-8-nonenyl group, 2,5-dimethyl-8-nonenyl group, 5,5-dimethyl-8-nonenyl group, 2,5,5-trimethyl-8
-Nonenyl group, 4-methyl-8-nonenyl group, 2,4-
Dimethyl-8-nonenyl group, 5-ethyl-8-nonenyl group, 5-ethyl-2-methyl-8-nonenyl group, 3-methyl-8-nonenyl group, 2,3-dimethyl-8-nonenyl group, 2,3,3-trimethyl-8-nonenyl group, 3-methyl-7-nonenyl group 2,3-dimethyl-7-nonenyl group, 3,3-dimethyl-7-nonenyl group, 2,3,3
3-trimethyl-7-nonenyl group, 4-methyl-7-nonenyl group, 2,4-dimethyl-7-nonenyl group, 4,4
-Dimethyl-7-nonenyl group, 5-methyl-7-nonenyl group, 2,5-dimethyl-7-nonenyl group, 5,5-dimethyl7-nonenyl group, 2,5,5-trimethyl-7-nonenyl group, 6-methyl-7-nonenyl group, 2,6 -Dimethyl-7-nonenyl group, 6,6-dimethyl-7-nonenyl group, 2,6,6-trimethyl-7-nonenyl group, 3
-Methyl-6-nonenyl group, 2,3-dimethyl-6-nonenyl group, 4-methyl-6-nonenyl group, 2,4-dimethyl-6-nonenyl group, 4,4-dimethyl-6-nonenyl group, 2,4,4-trimethyl-6-nonenyl group, 5 -Methyl-6-nonenyl group, 2,5-dimethyl-6-nonenyl group, 8-methyl-6-nonenyl group, 2,8-dimethyl-6-nonenyl group, 8,8-dimethyl-6-nonenyl group, 2,8,8-trimethyl-6-nonenyl group, 3-methyl- 5-nonenyl group, 2,3-dimethyl-5-nonenyl group, 3,3-dimethyl-5-nonenyl group, 2,3,3
-Trimethyl-5-nonenyl group, 4-methyl-5-nonenyl group, 2,4-dimethyl-5-nonenyl group, 4,4-
Dimethyl-5-nonenyl group, 2,4,4-trimethyl-5-nonenyl group, 7-methyl-5-nonenyl group, 2,7
-Dimethyl-5-nonenyl group, 7-ethyl-5-nonenyl group, 7-ethyl-2-methyl-5-nonenyl group, 8-methyl-5-nonenyl group, 2,8-dimethyl-5-nonenyl group, 8,8-dimethyl-5-nonenyl group, 2,8,8,
8-trimethyl-5-nonenyl group, 3-methyl-4-nonenyl group, 2,3-dimethyl-4-nonenyl group, 6-methyl-4-nonenyl group, 2,6-dimethyl-4-nonenyl group, 6,6-dimethyl-4-nonenyl group, 2,6,6
-Trimethyl-4-nonenyl group, 7,7-dimethyl-4
Examples thereof include a -nonenyl group, a 2,7,7-trimethyl-4-nonenyl group, a 7-ethyl-4-nonenyl group and a 7-ethyl-2-methyl-4-nonenyl group. Among these, C _{4 to} C ₁₀ alkenyl groups, especially C _{5 to} C ₁₀
Alkenyl groups are preferred.

Further, the unsubstituted C ₃ -C ₁₂ alkynyl group for R ²¹ is, for example, 3-butynyl group, 2-methyl-3-butynyl group, 3-pentynyl group, 2-methyl-3 group.
-Pentynyl group, 4-pentynyl group, 2-methyl-4-pentynyl group, 2,3-dimethyl-4-pentynyl group,
3-methyl-4-pentynyl group, 3-ethyl-2-methyl-4-pentynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 2-methyl-3-hexynyl group, 2-methyl-4-hexynyl group, 2-methyl-5
-Hexynyl group, 5-methyl-3-hexynyl group, 5,
5-dimethyl-hexynyl group, 2,5-dimethyl-3-hexynyl group, 2,3-dimethyl-4-hexynyl group,
4-methyl-5-hexynyl group, 2,4-dimethyl-5
-Hexynyl group, 4,4-dimethyl-5-hexynyl group, 2,4,4-trimethyl-5-hexynyl group, 3-methyl-5-hexynyl group, 2,3-dimethyl-5-hexynyl group, 3-heptynyl group, 4-heptynyl group, 5
-Heptinyl group, 6-heptynyl group, 2-methyl-3-heptynyl group, 2-methyl-4-heptynyl group, 2-methyl-5-heptinyl group, 2-methyl-6-heptynyl group, 5-methyl-6-heptinyl group, 2,5-dimethyl-6-heptynyl group, 5,5- Dimethyl-6-heptynyl group, 2,5,5-trimethyl-6-heptynyl group, 5
-Ethyl-6-heptinyl group, 5-ethyl-2-methyl-6-heptynyl group, 4-methyl-6-heptynyl group,
2,4-dimethyl-6-heptinyl group, 4,4-dimethyl-6-heptinyl group, 2,4,4-trimethyl-6-heptinyl group, 3-methyl-6-heptinyl group, 2,3
-Dimethyl-6-heptynyl group, 6-methyl-4-heptynyl group, 2,6-dimethyl-4-heptynyl group, 6,
6-dimethyl-4-heptynyl group, 2,6,6-trimethyl-4-heptynyl group, 3-methyl-5-heptynyl group, 2,3-dimethyl-5-heptinyl group, 3-methyl-4-heptynyl group, 5-methyl-3-heptynyl group,
2,5-dimethyl-3-heptynyl group, 3-octynyl group, 4-octynyl group, 5-octynyl group, 6-octynyl group, 7-octynyl group, 2-methyl-3-octynyl group, 2-methyl-4-octynyl group, 2-methyl-5
-Octynyl group, 2-methyl-6-octynyl group, 2-methyl-7-octynyl group, 6-methyl-7-octynyl group, 2,6-dimethyl-7-octynyl group, 6,6-
Dimethyl-7-octynyl group, 2,6,6-trimethyl-7-octynyl group, 5-methyl-7-octynyl group,
2,5-dimethyl-7-octynyl group, 4-methyl-7
-Octynyl group, 2,4-dimethyl-7-octynyl group, 4,4-dimethyl-7-octynyl group, 2,4,4
-Trimethyl-7-octynyl group, 3-methyl-7-octynyl group, 2,3-dimethyl-7-octynyl group,
3,3-Dimethyl-7-octynyl group, 2,3,3-trimethyl-7-octynyl group, 3-methyl-6-octynyl group, 2,3-dimethyl-6-octynyl group, 4-methyl-6-octynyl group, 2,4-dimethyl-6-octynyl group, 4 , 4-dimethyl-6-octynyl group, 2,
4,4-trimethyl-6-octynyl group, 5-methyl-6-octynyl group, 2,5-dimethyl-6-octynyl group, 5,5-dimethyl-6-octynyl group, 5,5,5
-Trimethyl-6-octynyl group, 7-methyl-5-octynyl group, 2,7-dimethyl-5-octynyl group, 4
-Methyl-5-octynyl group, 2,4-dimethyl-5-octynyl group, 4,4-dimethyl-5-octynyl group,
2,4,4-trimethyl-5-octynyl group, 7,7-
Dimethyl-5-octynyl group, 2,7,7-trimethyl-5-octynyl group, 6-methyl-4-octynyl group,
2,6-dimethyl-4-octynyl group, 6-ethyl-4
-Octynyl group, 6-ethyl-2-methyl-4-octynyl group, 6,6-dimethyl-4-octynyl group, 2,
6,6-trimethyl-4-octynyl group, 5-methyl-3-octynyl group, 2,5-dimethyl-3-octynyl group, 6-methyl-3-octynyl group, 2,6-dimethyl-3-octynyl group, 7-methyl-3-octynyl group,
2,7-Dimethyl-3-octynyl group, 3-nonynyl group, 4-nonynyl group, 5-nonynyl group, 6-nonynyl group, 7-nonynyl group, 8-nonynyl group, 2-methyl-3
Nonyl group, 2-methyl-4-nonynyl group, 2-methyl-5-nonynyl group, 2-methyl-6-nonynyl group, 2-methyl-7-nonynyl group, 2-methyl-8-nonynyl group, 7-methyl-8-nonynyl group, 2,7-dimethyl-8-nonynyl group, 7, 7-dimethyl-8-nonynyl group,
2,7,7-Trimethyl-8-nonynyl group, 6-methyl-8-nonynyl group, 2,6-dimethyl-8-nonynyl group, 6,6-dimethyl-8-nonynyl group, 2,6,6-
Trimethyl-8-nonynyl group, 5-methyl-8-nonynyl group, 2,5-dimethyl-8-nonynyl group, 5,5-dimethyl-8-nonynyl group, 2,5,5-trimethyl-8
-Noninyl group, 4-methyl-8-nonynyl group, 2,4-
Dimethyl-8-nonynyl group, 5-ethyl-8-nonynyl group, 5-ethyl-2-methyl-8-nonynyl group, 3-methyl-8-nonynyl group, 2,3-dimethyl-8-nonynyl group, 2,3,3-trimethyl-8-nonynyl group, 3-methyl-7-nonynyl group 2,3-dimethyl-7-nonynyl group, 3,3-dimethyl-7-nonynyl group, 2,3,3
3-trimethyl-7-nonynyl group, 4-methyl-7-nonynyl group, 2,4-dimethyl-7-nonynyl group, 4,4
-Dimethyl-7-noninyl group, 5-methyl-7-noninyl group, 2,5-dimethyl-7-noninyl group, 5,5-dimethyl-7-noninyl group, 2,5,5-trimethyl-7-noninyl group, 6-methyl-7-noninyl group, 2,6 -Dimethyl-7-nonynyl group, 6,6-dimethyl-7-nonynyl group, 2,6,6-trimethyl-7-nonynyl group, 3
-Methyl-6-nonynyl group, 2,3-dimethyl-6-nonynyl group, 4-methyl-6-nonynyl group, 2,4-dimethyl-6-nonynyl group, 4,4-dimethyl-6-nonynyl group, 2,4,4-trimethyl-6-nonynyl group, 5 -Methyl-6-nonynyl group, 2,5-dimethyl-6-nonynyl group, 8-methyl-6-nonynyl group, 2,8-dimethyl-6-nonynyl group, 8,8-dimethyl-6-nonynyl group, 2,8,8-trimethyl-6-nonynyl group, 3-methyl- 5-nonynyl group, 2,3-dimethyl-5-nonynyl group, 3,3-dimethyl-5-nonynyl group, 2,3,3
-Trimethyl-5-nonynyl group, 4-methyl-5-nonynyl group, 2,4-dimethyl-5-nonynyl group, 4,4-
Dimethyl-5-nonynyl group, 2,4,4-trimethyl-5-nonynyl group, 7-methyl-5-nonynyl group, 2,7
-Dimethyl-5-nonynyl group, 7-ethyl-5-nonynyl group, 7-ethyl-2-methyl-5-nonynyl group, 8-methyl-5-nonynyl group, 2,8-dimethyl-5-nonynyl group, 8,8-dimethyl-5-nonynyl group, 2,8,8
8-trimethyl-5-nonynyl group, 3-methyl-4-nonynyl group, 2,3-dimethyl-4-nonynyl group, 6-methyl-4-nonynyl group, 2,6-dimethyl-4-nonynyl group, 6,6-dimethyl-4-nonynyl group, 2,6,6-
Examples thereof include a trimethyl-4-nonynyl group, a 7,7-dimethyl-4-nonynyl group, a 2,7,7-trimethyl-4-nonynyl group, a 7-ethyl-4-nonynyl group and a 7-ethyl-2-methyl-4-nonynyl group. Among these, C _{4 to} C ₁₀ alkynyl groups, especially C _{5 to} C ₁₀
Alkynyl groups are preferred.

These R ²¹ substituents include fluorine,
A halogen atom such as chlorine: a lower alkoxy group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group: a cyclopentyl group, a C ₃ -C ₈ cycloalkyl group such as a cyclohexyl group and the like. Of these, a lower alkoxy group and a cycloalkyl group are preferable.

In R ²¹ for R ^{2 in the} above formula [1], R ²¹ is preferably a C ₃ -C ₇ linear or branched alkyl group. Examples of the C ₃ -C ₇ alkyl group include n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, 2-methylhexyl group, 2-methylpentyl group and the like. You can

R ^{2 in the} above formula [1] is (C
R ²² when it represents an H _{2) n} R ²² represents a cycloalkyl group which may C ₃ -C ₁₀ substituted. Specific examples of the cycloalkyl group in this case include a cyclopentyl group and a cyclohexyl group, and among them, a C ₃ -C ₈ cycloalkyl group, particularly a C ₄ -C ₇ cycloalkyl group is preferable. As the substituent, for example, a methyl group,
C ₁ -C ₆ lower alkyl group such as ethyl group, propyl group and hexyl group: halogen atom such as fluorine and chlorine: lower alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group: trifluoromethyl group, etc. And halogenated lower alkyl groups. In addition, n represents the integer of 0-2.

In the above formula [1], R ³ and R ⁴ are
Each of them is independent of each other, that is, the same or different and represents a hydrogen atom or the formula "2". R ⁵ in the formula “2” represents a C _{1 to} C ₅ linear or branched alkyl group, and examples thereof include the same ones as those of R ² . As R ⁵ , a C ₁ -C ₃ alkyl group is preferable, and a straight chain is particularly preferable. In addition, as R ⁵ ,
A methyl group is particularly preferable. A hydrogen atom is particularly preferable as R ³ and R ⁴ .

The configurations of the 8-, 9-, 11-, 12- and 15-positions of the prostacyclins represented by the above formula [1] are the same as those of natural prostacyclin and are particularly useful stereoisomers. However, in the present invention, stereoisomers due to different steric configurations at each position, or a mixture of them at an arbitrary ratio are included.

Specific preferred examples of the prostacyclins used in the present invention are as follows. (1) 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (2) 20-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (3) 19,20 Jinoru 9 (O) -Methano △ ^{6 (9}
α ⁾ -prostaglandin I ₁ (4) 20-norrho 9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (5) 19-methyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (6) 18-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (7) 20-ethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (8) 20 -Isopropyl-9 (O) -methano ^{6 (9}
α ⁾ -Prostaglandin I ₁ (9) 20-Methyl-20-Ethyl-9 (O) -Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (10) 19-Methyl-20-Ethyl-9 (O) -Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁

(11) 18-methyl-20-ethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (12) 20-propyl-9 (O) Metano △ ^{6 (9 α)}
-Prostaglandin I ₁ (13) 22-Methyl-20-propyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁ (14) 21-Methyl-20-propyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -Prosta Glandin I ₁ (15) 20-Methyl-20-propyl-9 (O) -methanone Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (16) 19-methyl-20-propyl-9 (O) -methanone Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (17) 18-Methyl-20-propyl-9 (O) -methanone Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (18) 20-norru 18-methylene-9 (O) -methanoe Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (19) 20-norru 18,19-didehydro-9
(O) -Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (20) 18,19-Didehydro-9 (O) -methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁

[0024] (21) 18,19 Jidehidoro 20-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (22) 18,19 Jidehidoro 20-ethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (23) 18,19- Jidehidoro 20-propyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (24) 18,19- Jidehidoro 20-butyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (25) 18 Mechiren 20-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (26) 18,19- Jidehidoro 20, 20- dimethyl 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (27) 18,19- Jidehidoro 20- methyl-20
-Ethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (28) 18,19- Jidehidoro 20-isopropyl -20-ethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ ( 29) 18,19-didehydro-20-methyl-20
-Butyl-9 (O) -methanone Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (30) 18,19-didehydro-20- (1-methylpropyl) -9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁

(31) 18,19-didehydro-20-
Methyl-20-propyl-9 (O) -methanoe △ ^{6 (} 9α ⁾
Over prostaglandin I ₁ (32) 18,19- Jidehidoro 20,20-dimethyl-20-butyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (33) 19,20- Jidehidoro 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (34) 19,20- Jidehidoro 20-methyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (35) 19,20- Jidehidoro 19-methyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (36) 19,20- Jidehidoro 20-ethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (37) 19,20- Jidehidoro 20-propyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (38) 19,20- Jidehidoro 20-butyl-9
(O) -Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (39) 19,20-Didehydro-18,20-dimethyl-9 (O) -methano Δ Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (40) 19, 20- Jidehidoro 20-1 (1 over methylpropyl) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁

[0026] (41) 19,20- Jidehidoro 20-1 isopropyl over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (42) 19,20- Jidehidoro 20-1 (2 Mechirubuchiru) over 9 (O) Metano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (43) 19,20-didehydro-20- (1,1-dimethylpropyl) -9 (O) -methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (44 ) 20-methylene-9 (O) -methanoe △ ^{6 (9} α ⁾
-Prostaglandin I ₁ (45) 20-Methyl-20-methylene-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (46) 19-methyl-20-methylene-9 (O) -methano Δ- ^{6 (9} α ⁾ -prosta Grangen I ₁ (47) 20-Ethylidene-9 (O) -Methano △ ^{6 (9}
α ⁾ -Prostaglandin I ₁ (48) 20-Propylidene-9 (O) -Methano △
^{6 (9} α ⁾ -prostaglandin I ₁ (49) 20-butylidene-9 (O) -methanone △ ^{6 (9}
α ⁾ -Prostaglandin I ₁ (50) 20- (1-Ethylbutylidene) -9 (O) -methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁

(51) 20- (1-methylbutylidene)
ー 9 (O) ー Methano △ ^{6 (9} α ⁾ー Prostaglandin I
₁ (52) 20-1 (1 over methylethylidene) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (53) 19-methyl-20 Puropiriden 9 (O)
-Methano- ^{6 (} 9α ⁾ -Prostaglandin I ₁ (54) 20- (2-Methylpropylidene ⁾ -9 (O)
-Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (55) 19-Methyl-20-butylidene-9 (O) -Methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁ (56) 20- (3-methylbutylidene)- 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (57) 19,19-dimethyl-20 Mechiren 9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (58) 20 Biniru 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (59) 19-methyl-20 Biniru 9 (O) Metano △ ^{6 (9} α ⁾ -Prostaglandin I ₁ (60) 19,19-Dimethyl-20-Vinyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

(61) 20-methyl-20-vinyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (62) 20 chromatography (1 over methylvinyl) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (63) 20 chromatography (1 Puropeniru) -9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (64) 20 chromatography (2-methyl-1 Puropeniru) -9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (65) 19-methyl-20 chromatography (1 Puropeniru) -9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (66) 19, 19-dimethyl-20 chromatography (1 Puropeniru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (67) 19-methyl-20 chromatography (2-methyl-1 Puropeniru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (68) 18-methyl-20 chromatography (2-methyl-1 Puropeniru) over 9 (O) Metano △ ^{6 ( 9} α ⁾ -Prostaglandin I ₁ (69) 18,18-Dimethyl-20- (2-methyl-1-propenyl) -9 (O) -methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁ (70) 20- (1-butenyl ) -9 (O) -Methano △ ^{6 (9} α ⁾ -Prostaglandin I ₁

(71) 20- (2-methyl-1-butenyl) -9 (O) -methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (72) 20- (2-ethyl-1-butenyl) -9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (73) 20-methyl-20 chromatography (1 Buteniru) -9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (74) 19-methyl-20 chromatography (1 Buteniru) -9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (75) 19, 19-dimethyl-20 chromatography (1 Buteniru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (76) 20-norru 18,19-tetradehydro-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (77) 18,19- tetramethyl-dehydro low 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (78) 18,19- tetra dehydro low 20-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (79) 18,19-tetra dehydro low 20-ethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (80) 18,19-tetra dehydro low 20-1 (2 Mechirubuchiru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁

(81) 18,19-tetradehydro-2
0-Propyl-9 (O) -methanore Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (82) 18,19-tetradehydro-20,20-dimethyl-9 (O) -methanoe Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (83) 18,19-Tetradehydro-20,20,2
0-trimethyl-9 (O) -methanore Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (84) 18,19-tetradehydro-20-methyl-20-ethyl-9 (O) -methanoe Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (85) 18,19-tetra dehydro low 20,20-dimethyl-20-ethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (86) 18,19-tetra dehydro low 20,20 Jiechiru 9 ( O) -Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (87) 18,19-Tetradehydro-20-isopropyl-9 (O) -methano Δ Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (88) 18,19 - tetra dehydro low 20-1 t- butyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (89) 18,19- tetramethyl-dehydro row 20 Mechi -20-propyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (90) 18,19- tetramethyl-dehydro low 20,20-dimethyl-20-propyl-9 (O) Metano △ ^{6 (9 α)}
-Prostaglandin I ₁

(91) 18,19-tetradehydro-2
0- (2-methylpropyl) -9 (O) -methano △
^{6 (9} α ⁾ -prostaglandin I ₁ (92) 18,19-tetradehydro-20- (2,2
- dimethylpropyl) over 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (93) 18,19-tetra dehydro low 20-methyl-20-butyl-9 (O) Metano △ ^{6 (9 α)} Purosuta Glandin I ₁ (94) 18,19-tetradehydro-20,20-9
(O) -Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (95) 18,19-Tetradedehydro-20- (2-methylbutyl) -9 (O) -methano Δ Δ ^{(6 (9} α ⁾ -Prostaglandin I ₁ (96) 18,19-tetra dehydro low 20-1 (2 Echirubuchiru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (97) 18,19-tetra dehydro low 20-1 (2,2
Over-dimethylbutyl) over 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (98) 19,20- tetramethyl-dehydro low 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (99) 19,20- tetra dehydro low 18-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (100) 19,20- tetramethyl-dehydro low 18,20-dimethyl-9 (O) Metano △ ^{6 (9} α ⁾ー Prostaglandin I ₁

[0032] (101) 19,20- tetramethyl-dehydro low 20-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (102) 19,20- tetramethyl-dehydro low 20-ethyl-9 (O) Metano △ ^{6 (9} α ⁾ -Prostaglandin I
₁ (103) 19,20- tetramethyl-dehydro low 20-1 isopropyl over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (104) 19,20- tetramethyl-dehydro low 20-1 t- butyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (105) 19,20- tetramethyl-dehydro low 20-propyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (106) 19,20- Tetoradehido low 20-1 (1 over methylpropyl) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (107) 19,20- tetramethyl-dehydro low 20-1 (1 over ethylpropyl) over 9 (O) Metano △ ^{6 ( 9} α ⁾ -prostaglandin I ₁ (108) 19,20-tetradehydro-20- (1,
1-Dimethylpropyl) -9 (O) -methanoe △ ^{6 (9} α ⁾
Over prostaglandin I ₁ (109) 19,20- tetramethyl-dehydro low 20-butyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I
₁ (110) 19,20- tetramethyl-dehydro low 18-dimethyl-20-butyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁

(111) 19,20-Tetradehydro-20- (1-methylbutyl) -9 (O) -methano Δ
^{6 (9} α ⁾ -prostaglandin I ₁ (112) 19,20-tetradehydro-20- (1,
-1-dimethylbutyl) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (113) 19,20- tetramethyl-dehydro low 20-1 (2,
2-dimethylbutyl) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (114) 19,20- tetramethyl-dehydro low 20-1 (2 Echirubuchiru) over 9 (O) Metano △ ^{6 (9 alpha)} over Prostaglandin I ₁ (115) 19,20-Tetradehydro-18-methyl-20-propyl-9 (O) -methano Δ △ ^{6 (9} α ⁾ -Prostaglandin I ₁ (116) 20-methylidin-9 (O) -methano △
^{6 (9 α)} over prostaglandin I ₁ (117) 20- Mechirijin 18-methyl-9 (O)
-Methano △ ^{6 (9} α ⁾ -Prostaglandin I ₁ (118) 20-Ethirizine-9 (O) -Methano Δ
^{6 (9 α)} over prostaglandin I ₁ (119) 20- pro pyridine over 9 (O) Metano △
^{6 (9} α ⁾ -Prostaglandin I ₁ (120) 20- (2-Methylpropyridin) -9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

[0034] (121) 20-pro pyridine over 19-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (122) 20-(2,2-dimethyl-pro pyridine) over 9 (O) Metano △ ^{6 (9} α ⁾ -Prostaglandin I ₁ (123) 20-Prolidine-19,19-Dimethyl-9 (O) -methano Δ △ ^{6 (9} α ⁾ -Prostaglandin I ₁ (124) 20-Butyridin-9 (O) -methano △
^{6 (9 α)} over prostaglandin I ₁ (125) 20- Buchirijin 18-methyl-9 (O)
-Methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (126) 20-butyridine-18,18-dimethyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (127) 20-butyridine-19-methyl-9 ( O)
Metano △ ^{6 (9 α)} over prostaglandin I ₁ (128) 20- Buchirijin 19,19-dimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (129) 20- (2 Mechirubuchi Lysine) -9 (O)
-Methano- ^{6 (} 9α ⁾ -Prostaglandin I ₁ (130) 20- (2-Ethylbutyridine ⁾ -9 (O)
-Methano △ ^{6 (9} α ⁾ -Prostaglandin I ₁

[0035] (131) 20- (3-methylstyrene butyrate lysine) -9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (132) 20- (3,3-dimethyl-butyl-lysine) -9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (133) 20- Echiniru 9 (O) Metano △ ^{6 (9}
α ⁾ -prostaglandin I ₁ (134) 20-ethynyl-18-methyl-9 (O) -methano Δ6 ⁽⁹ α ⁾ -prostaglandin I ₁ (135) 20-ethynyl-19-methyl-9 (O) -methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (136) 20-ethynyl-19,19-dimethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (137) 20- Echiniru 20-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (138) 20- Echiniru 20,20 -Dimethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (139) 20- ₍₁ over propynyl) over 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (140) 20- ₍₁ -Propinyl) -18-methyl-9 (O) -methanog △ ^{6 (9} α ⁾ -prostaglandin I ₁

(141) 20- (1-propynyl) -1
9-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (142) 20- (1 over propynyl) over 19-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (143) 20- (1 over propynyl) -20-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (144) 20- (1 over propynyl) over 20,20-dimethyl-9 (O) Metano △ ^{6 (9} α ⁾ -Prostaglandin I ₁ (145) 20- (1-butynyl) -9 (O) -methano Δ6 ⁽⁹ α ⁾ -Prostaglandin I ₁ (146) 20- (1-butynyl) -18-methyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (147) 20- ₍₁ Buchiniru) over 19-methyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (148) 20- ₍₁ Buchiniru) -20-methyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (149) 20- ₍₁ Buchiniru) over 19-dimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (0.99) 20- (3-methyl-1-butynyl) -9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

(151) 20- (3,3-dimethyl-1
Buchiniru) over 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (152) 20- (2 Buchiniru) over 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (153) 20- (2-propynyl) over 18-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (154) 20- (2-propynyl) over 18-dimethyl-9 (O) Metano △ ^{6 (9} alpha ⁾ over prostaglandin I ₁ (155) 20- (2 chromatography propynyl) over 19-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (156) 20- (2 chromatography propynyl) over 19,19-dimethyl- 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (157) 20- (2 chromatography propynyl) -20-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ ( 58) 20- (1-methyl-2-propynyl) -9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (159) 20- (1,1- dimethyl-2-propynyl) over 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (160 ) 20- (2-butynyl) -18-methyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

(161) 20- (2-butynyl) -1
8,18-dimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (162) 20- (2 Buchiniru) over 19-dimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin _{I 1 (161 ') 20- (} 2 Buchiniru) over 20,20-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin _{I 1 (162') 20- (} 1 -methyl-2 Buchiniru) -9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (163) 20- (1,1- dimethyl-2 Buchiniru)
ー 9 (O) ー Methano △ ^{6 (9} α ⁾ー Prostaglandin I
₁ (164) 20- (3 Buchiniru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (165) 20- (3 Buchiniru) over 18-dimethyl-9 (O) Metano △ ^{6 ( 9} α ⁾ -Prostaglandin I ₁ (166) 20- (3-butynyl) -18-methyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (167) 20- (3 Buchiniru) -20-methyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (168) 20- (2-methyl-3 Buchiniru) -9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (169) 20- (2,2- dimethyl-3 Buchiniru)
ー 9 (O) ー Methano △ ^{6 (9} α ⁾ー Prostaglandin I
₁ (170) 20- (1,1-dimethyl-3-butynyl)
ー 9 (O) ー Methano △ ^{6 (9} α ⁾ー Prostaglandin I
₁

(171) 16, 17, 18, 19, 20
-Pentanolou 15-cyclopentyl-9 (O) -methano Δ ^{(6 (} 9α ⁾⁾ -prostaglandin I ₁ (172) 16,17,18,19,20-pentanolou 15-cyclohexyl-9 (O) -methano Δ ^{(6 (9} ) α ⁾
Over prostaglandin I ₁ (173) 16,17,18,19,20- Pentanoru 15 chromatography (2-chloro-cyclopentyl) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (174) 16 , 17,18,19,20-Pentanolu 15- (3-trifluoromethylcyclohexyl) -9 (O) -methano Δ △ ^{6 (9} α ⁾ -prostaglandin I ₁ (175) 17-ethoxy-9 (O) -methano △ ^{6 (9}
α ⁾ -Prostaglandin I ₁ (176) 17-Methyl-9 (O) -methano Δ- ^{6 (9} α ^).
-Prostaglandin I ₁ (177) 17 (R) -Methyl-9 (O) -Methano Δ
^{6 (9 α)} over prostaglandin _{I 1 (178) 17 (S} ) - methyl-9 (O) Metano △
^{6 (9 α)} over prostaglandin I ₁ (179) 20 Noru 17- methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (180) 17,19-dimethyl-9 (O) Metano △ ^{6 (9} α ⁾ -Prostaglandin I ₁

(181) 17,18-dimethyl-9
(O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (182) 17-methyl-20-ethyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (183) 17-methyl-20-isopropyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (184) 17,20-dimethyl-20-ethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (185) 17,19-dimethyl-20-ethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (186) 17,18-dimethyl-20-ethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (187) 17-methyl-20-propyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (188) 17,22-dimethyl-20-propyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (189) 17,21-dimethyl-20-propyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (190) 17,20-dimethyl-20-propyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

[0041] (191) 17, 19-dimethyl-20-propyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (192) 17, 18-dimethyl-20-propyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (193) 20 Noru 17-methyl-18 Mechiren 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I
₁ (194) 20-Nolu 18,19-Didehydro-17
-Methyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (195) 18,19-didehydro-17-methyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (196) 18,19 Jidehidoro 17,20- dimethyl 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (197) 18, 19-didehydro-20-ethyl-1
7- methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (198) 18,19 Jidehidoro 20-propyl-17-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ ( 199) 18,19-didehydro-20-butyl-1-
7- methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (200) 18 Mechiren 17,20- dimethyl 9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

(201) 18,19-didehydro-1
7,20,20-Trimethyl-9 (O) -methanone △
^{6 (9} α ⁾ -Prostaglandin I ₁ (202) 18,19-didehydro-17,20-dimethyl-20-ethyl-9 (O) -methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (203) 18,19-didehydro-20 - isopropyl over 17-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (204) 18,19 Jidehidoro 17,20- dimethyl 20-butyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandins Gin I ₁ (205) 18,19-didehydro-17-methyl-2
0- (1-methylpropyl) -9 (O) -methano △
^{6 (9} α ⁾ -prostaglandin I ₁ (206) 18,19-didehydro-17,20-dimethyl-20-propyl-9 (O) -methano Δ6 ⁽⁹ α ⁾ -prostaglandin I ₁ (207) 18,19-didehydro-17 , 20, 20
-Trimethyl-20-butyl-9 (O) -methano
^{6 (9} α ⁾ -prostaglandin I ₁ (208) 19,20-didehydro-17-methyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (209) 19,20 Jidehidoro 17,20- dimethyl 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (210) 19, 20 Jidehidoro 17,19- dimethyl 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

(211) 19,20-didehydro-17
-Methyl-20-ethyl-9 (O) -methanoe △ ^{6 (} 9α ⁾
-Prostaglandin I ₁ (212) 19,20-Didehydro-17-methyl-2
0 Puropiru 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (213) 19,20 Jidehidoro 17- methyl-2
0-Butyl-9 (O) -methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (214) 19,20-didehydro-17,18,20
- trimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (215) 19,20 Jidehidoro 17- methyl-2
0- (1-methylpropyl) -9 (O) -methano △
^{6 (9} α ⁾ -prostaglandin I ₁ (216) 19,20-didehydro-17-methyl-2
0-Isopropyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (217) 19,20-didehydro-17-methyl-2
0- (2-methylbutyl) -9 (O) -methanone △ ^{6 (9}
α ⁾ -Prostaglandin I ₁ (218) 19,20-Didehydro-17-methyl-2
0- (1,1-dimethylpropyl) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (219) 17-methyl-20-Mechiren 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandins Gin I ₁ (220) 17,20-dimethyl-20-methylene-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

(221) 17,19-dimethyl-20-
Mechiren 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (222) 17-methyl-20 chromatography ethylidene over 9 (O)
Metano △ ^{6 (9 α)} over prostaglandin I ₁ (223) 17-methyl-20 Puropiriden 9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (224) 17-methyl-20 Buchiriden 9 (O)
-Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (225) 17-Methyl-20- (1-ethylbutylidene) -9 (O) -Methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁ (226) 17-methyl- 20- (1-Methylbutylidene) -9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (227) 17-methyl-20- (1-methylethylidene) -9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (228) 17,19-dimethyl-20-propylidene-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I
₁ (229) 17-methyl-20 chromatography (2-methyl propylidene) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (230) 17, 19-dimethyl-20 Buchiriden 9 (O) Metano △ ^{6 ( 9} α ⁾ -Prostaglandin I ₁

[0045] (231) 17-methyl-20 chromatography (3-methylstyrene butylidene) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (232) 17,19,19 Torimechiru 20- Mechiren 9 (O ) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (233) 17-methyl-20 Biniru 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (234) 17,19-dimethyl-20-vinyl-9
(O) -Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (235) 17,19,19-Trimethyl-20-vinyl-9 (O) -methano Δ Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (236) 17,20 -Dimethyl-20-Vinyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (237) 17-methyl-20-1 (1-methylstyrene-vinyl)
ー 9 (O) ー Methano △ ^{6 (9} α ⁾ー Prostaglandin I
₁ (238) 17-methyl-20 chromatography (1 Puropeniru) over 9 (O) Metano over △ ^{6 (9 alpha)} over prostaglandin I ₁ (239) 17-methyl-20 chromatography (2-methyl-1 Puropeniru) over 9 (O) Metano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (240) 17,19-Dimethyl-20- (1-propenyl) -9 (O) -methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁

(241) 17,19,19-Trimethyl-20- (1-propenyl) -9 (O) -methano Δ
^{6 (9} α ⁾ -prostaglandin I ₁ (242) 17,19-dimethyl-20- (2-methyl-1-propenyl) -9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (243) 17,18 dimethyl-20 chromatography (2-methyl-1 Puropeniru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (244) 17,18,18 Torimechiru 20-1 (2
-Methyl-1-propenyl) -9 (O) -methanone △
^{6 (9} α ⁾ -prostaglandin I ₁ (245) 17-methyl-20- (1-butenyl) -9
(O) Metano over △ ^{6 (9 alpha)} over prostaglandin I ₁ (246) 17-methyl-20 chromatography (2-methyl-1 Buteniru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (247 ) 17-methyl-20 chromatography (2-ethyl-1 Buteniru) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (248) 17,20-dimethyl-20 Buteniru 9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (249) 17,19-dimethyl-20 Buteniru 9
(O) -Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (250) 17,19,19-Trimethyl-20-butenyl-9 (O) -Methanol Δ ^{6 (9} α ⁾ -Prostaglandin I ₁

(251) 20-norru 18,19-tetradehydro-17-methyl-9 (O) -methano Δ ^{6 (9}
α ⁾ -prostaglandin I ₁ (252) 18,19-tetradehydro-17-methyl-9 (O) -methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (253) 18,19-tetradehydro-17,20 dimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (254) 18,19 chromatography tetra dehydro low 17-methyl-20-ethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ ( 255) 18,19 chromatography tetra dehydro low 17-methyl-20-butyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (256) 18,19 chromatography tetra dehydro low 17-methyl-20-propyl-9 (O) Metano △ ^{6 (9} α ⁾ -prostaglandin I ₁ (257) 18,19-tetradehydro-17,20,
20 Torimechiru 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (258) 18,19 chromatography tetra dehydro low 17,20,
20,20-Tetramethyl-9 (O) -methanone △ ^{6 (9}
α ⁾ -prostaglandin I ₁ (259) 18,19-tetradehydro-17,20-dimethyl-20-ethyl-9 (O) -methano Δ- ^{6 (9} α ^).
-Prostaglandin I ₁ (260) 18,19-tetradehydro-17,20,
20 Torimechiru 20-ethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

[0048] (261) 18, 19 over tetra dehydrogenase low 17-methyl-20,20-diethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (262) 18,19 over tetra dehydrogenase low 17-methyl-20 over isopropyl over 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (263) 18,19 chromatography tetra dehydro low 17-methyl-20-1 t- butyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (264) 18,19-tetradehydro-17,20-dimethyl-20-propyl-9 (O) -methano Δ ^{6 (9}
α ⁾ -prostaglandin I ₁ (265) 18,19-tetradehydro-17,20,
20-trimethyl-20-propyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (266) 18, 19 over tetra dehydro low 17-methyl-20 chromatography (2-methylpropyl) over 9 (O) Metano △ ^{6 (9} α ⁾ -prostaglandin I ₁ (267) 18,19-tetradehydro-17-methyl-20- (2,2-dimethylpropyl) -9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (268 ) 18,19-Tetradehydro-17,20-dimethyl-20-butyl-9 (O) -methanoe Δ ^{6 (9} α ^).
-Prostaglandin I ₁ (269) 18,19-Tetradehydro-17,20,
20 Torimechiru 20-butyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (270) 18, 19 over tetra dehydro low 17-methyl-20 chromatography (2-methylbutyl) over 9 (O) Metano △
^{6 (9} α ⁾ -Prostaglandin I ₁

(271) 18,19-tetradehydro-17-methyl-20- (2-ethylbutyl) -9 (O)
-Methano △ ^{6 (9} α ⁾ -Prostaglandin I ₁ (272) 18,19-Tetradehydro-17-methyl-20- (2,2-dimethylbutyl) -9 (O) -Methano Δ- ^{6 (9} α ⁾ -Prostaglandin Gin I ₁ (273) 19,20-Tetradedehydro-17-methyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I
₁ (274) 19,20-tetradehydro-17,18-dimethyl-9 (O) -methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (275) 19,20-tetradehydro-17,18,
20 Torimechiru 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (276) 19, 20 over tetra dehydro low 17,20-dimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (277) 19,20-Tetradehydro-17-methyl-20-ethyl-9 (O) -methanoe Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (278) 19,20-tetradehydro-17-methyl-20-isopropyl-9 (O) -methanoe △ ^{6 (9 α)} over prostaglandin I ₁ (279) 19,20 chromatography tetra dehydro low 17-methyl-20-1 t- butyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (280) 19 , 20-Tetradehydro-17-methyl-20-propyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁

(281) 19,20-Tetradehydro-17-methyl-20- (1-methylpropyl) -9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (282) 19, 20 over tetra dehydro low 17-methyl-20 chromatography (1 over ethylpropyl) over 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (283) 19,20-Tetradehydro-17-methyl-20- (1,1-dimethylpropyl) -9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (284) 19,20-tetra Dehidoro 17-methyl-20-butyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (285) 19,20 chromatography tetra dehydro low 17,18-dimethyl-20-butyl-9 (O) Metano △ ^{6 (9 α)}
-Prostaglandin I ₁ (286) 19,20-Tetradehydro-17-methyl-20- (1-methylbutyl) -9 (O) -methano Δ
^{6 (9} α ⁾ -Prostaglandin I ₁ (287) 19,20-Tetradehydro-17-methyl-20- (2,2-dimethylpropyl) -9 (O) -methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁ (288) 19,20-Tetradehydro-17-methyl-20- (2-ethylbutyl-9 (O) -methano
^{6 (9} α ⁾ -prostaglandin I ₁ (289) 19,20-tetradehydro-17,18-dimethyl-20-propyl-9 (O) -methanone Δ ^{6 (9}
α ⁾ -Prostaglandin I ₁ (290) 20-Methylidine-17-methyl-9 (O)
-Methano △ ^{6 (9} α ⁾ -Prostaglandin I ₁

(291) 20-methylidine-17,18
Dimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (292) 20 Mechirijin 17,20-dimethyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (293) 20 Echirijin 17ー Methyl-9 (O)
Metano △ ^{6 (9 α)} over prostaglandin I ₁ (294) 20 over pro pyridine over 17-methyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (295) 20 chromatography (2-methylpropionitrile pyridine) over 17-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (296 ) 20-Propyridine-17,19-dimethyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I
₁ (297) 20-1 (2,2 over dimethylpropionyl pyridine) over 17-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (298) 20 over pro pyridine over 17,19,19 Torimechiru 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (299) 20 Buchirijin 17-methyl-9 (O)
-Methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (300) 20-Butyridin-17,18-Dimethyl-9 (O) -Methano Δ- ^{6 (9} α ⁾ -Prostaglandin I ₁

(301) 20-Butyridin-17,1
8,18 Torimechiru 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (302) 20 Buchirijin 17,18,19 Torimechiru 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ ( 303) 20-Butyridin-17,19,19-trimethyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin I ₁ (304) 20-Butyridin-17,19-dimethyl-9 (O) -methano Δ- ^{6 (9} α ⁾ -prostaglandin Gin I ₁ (305) 20- (2-Methylbutyridine) -17-Methyl-9 (O) -methano Δ ^{6 (9} α ⁾ -Prostaglandin I ₁ (306) 20- (2-Ethylbutyridine) -17-Methyl- 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (307) 20 chromatography (3-methylstyrene butyrate lysine) over 17-methyl-9 (O) over Tano △ ^{6 (9 alpha)} over prostaglandin I ₁ (308) 20 chromatography (3,3 over dimethylbutyryl lysine) -1
7-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (309) 20 Echiniru 17-methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (310) 20 Echiniru 17, 18-dimethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

(311) 20-ethynyl-17,19-dimethyl-9 (O) -methano Δ6 ⁽⁹ α ⁾ -prostaglandin I ₁ (312) 20-ethynyl-17,19,19-trimethyl-9 (O) -methano Δ6 ⁽⁹ α) ⁾ -Prostaglandin I ₁ (313) 20-ethynyl-17,20-dimethyl-9
(O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (314) 20 Echiniru 17,20,20 Torimechiru 9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁ (315) 20 chromatography ( -1-propynyl) over 17-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (316) 20 chromatography (1 over propynyl) over 17-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} Purosuta prostaglandin I ₁ (317) 20 chromatography (1 over propynyl) over 17, 19-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (318) 20 chromatography (1 over propynyl) over 17,19,1
9 Torimechiru 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (319) 20 chromatography (1 over propynyl) over 17,20-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (320) 20- (1-propynyl) -17,20,2
0-trimethyl-9 (O) -methanone △ ^{6 (9} α ⁾ -prostaglandin I ₁

(321) 20- (1-butynyl) -17
-Methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (322) 20 chromatography (1 Buchiniru) over 17-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ ( 323) 20-1 (1 Buchiniru) over 17, 19-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (324) 20-1 (1 Buchiniru) over 17,19,19
Torimechiru 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (325) 20 chromatography (1 Buchiniru) over 17,20-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ ( 326) 20- (3-methyl-1-butynyl) -17
-Methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (327) 20 chromatography (3,3-dimethyl-1 Buchiniru)
Over 17-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (328) 20 chromatography (2 Buchiniru) over 17-methyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (322 ') 20 chromatography (2-propynyl) over 17-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (323 ') 20- (2-propynyl) -17,18,
18 Torimechiru 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (324 ') 20 chromatography (2-propynyl) over 17, 19-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (325 ') 20- (2-propynyl) -17,19,
19 Torimechiru 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (326 ') 20 chromatography (2-propynyl) over 17,20-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (327 ') 20-1 (1-methyl-2-propynyl) over 17-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (328') 20-1 (1,1-dimethyl-2-propynyl) over 17-methyl- 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (329) 20 chromatography (2 Buchiniru) over 17-methyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (330) 20 chromatography (2 Buchiniru) over 17-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁

(331) 20- (2-butynyl) -1
7,18,18-Trimethyl-9 (O) -methanone △
^{6 (9} α ⁾ -prostaglandin I ₁ (332) 20- (2-butynyl) -17,19,19
Torimechiru 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (333) 20 chromatography (2 Buchiniru) over 17,20,20
Torimechiru 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (334) 20 chromatography (1-methyl-2 Buchiniru) over 17
-Methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (335) 20 chromatography (1,1-dimethyl-2 Buchiniru)
Over 17-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (336) 20 chromatography (3 Buchiniru) over 17-methyl-9
(O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (337) 20 chromatography (3 Buchiniru) over 17-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (338) 20- (3-butynyl) -17,18,18
Torimechiru 9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (339) 20 chromatography (3 Buchiniru) over 17,20-dimethyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ ( 340) 20- (1-methyl-3-butynyl) -17
-Methyl-9 (O) Metano △ ^{6 (9 α)} over prostaglandin I ₁

(341) 20- (2-Methyl-3-butynyl) -17-methyl-9 (O) -methano Δ ^{6 (9} α ⁾ -prostaglandin I ₁ (342) 20- (1,1-dimethyl-3-butynyl)
Over 17-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (343) 20 chromatography (2,2-dimethyl-3 Buchiniru)
Over 17-methyl-9 (O) Metano △ ^{6 (9 alpha)} over prostaglandin I ₁ (344) (1) - ethyl ester (346) of (343) methyl ester of (345) (1) - (343) ( 1) to (343) butyl ester (347) (176) to (343) include those in which the methyl group at the 17-position is an ethyl group, but are not limited thereto.

The prostacyclin represented by the above formula [1] can be easily produced by a known method. The manufacturing method thereof is described in, for example, JP-A Nos. 59-210044 and 61.
-197518, etc.

The concentration of prostacyclin with respect to the total amount of ointment may be any as long as it has a therapeutic effect.
For example, the range of 0.000001% -0.1% is mentioned. The preferable range is 0.00001% to 0.01
%.

Examples of the higher paraffinic hydrocarbon used as a base include paraffin, white petrolatum, microcrystalline wax, liquid paraffin, light liquid paraffin, or a mixture of two or more thereof. Paraffin in the present invention means paraffin or paraffin wax. The liquid paraffin and light liquid paraffin in the present invention can be added for the purpose of adjusting the hardness (concentration) of the ointment while maintaining the drug efficacy. Paraffin is a percutaneous absorption,
The total amount is preferably in the range of 1 to 25% by weight, and particularly preferably in the range of 3 to 15% by weight in which significant improvement in transdermal absorbability is recognized. Further considering the consistency, the range of 3 to 10% by weight is most preferable.

The liquid paraffin is preferably in the range of 0 to 15% by weight in order to adjust the hardness of the ointment without impairing the sustained efficacy of the combination of petrolatum and paraffin. Furthermore, the range of 0 to 10% by weight is more preferable.

Examples of the fatty acid ester used as the solubilizer include higher fatty acid esters such as diisopropyl adipate, isopropyl palmitate, isopropyl myristate, ethyl linoleate, myristyl myristate, cetyl isooctanoate and octyldodecyl myristate, or For example, ethylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dioctanoate, medium chain fatty acid triglyceride,
Examples thereof include polyhydric alcohol esters of fatty acids such as tree 2-ethylhexanoate glycerin. Preferred fatty acid esters include, for example, diisopropyl adipate, isopropyl palmitate, isopropyl myristate, and the like.

The content of the solubilizer is preferably 0.01 to 1% by weight of the total amount of the ointment from the viewpoint of maintaining the drug effect, and 0.1 to 0.
A range of 5% by weight is preferred.

Preservatives such as paraoxybenzoic acid ester, sodium benzoate, salicylic acid, sorbic acid and boric acid, if necessary, in addition to the above-mentioned base and active ingredient;
Antioxidants such as butylhydroxyanisole and butylhydroxytoluene; surfactants, moisturizers, thickeners, fragrances, dyes and the like can be appropriately added within a range that does not impair the effects of the present invention.

The ointment can be manufactured by a conventional method. For example, prostacyclin is added to a solubilizer and dissolved. Examples include a method in which the solution is separately added to a highly paraffinic hydrocarbon that has been heated and melted, or a mixture of two or more kinds of these, and then the mixture is uniformly mixed and cooled.

The above-mentioned prostacyclin-containing composition is used for skin ulcers such as pressure ulcers, burn ulcers, vascular ulcers, diabetic ulcers, peripheral circulatory disorders, ulcers with collagen disease, and other ulcers and vibrational diseases, Buerger's disease. , And a therapeutic agent for peripheral circulatory failure such as Raynaud's disease. Incidentally, the prostacyclin-containing composition of the present invention was not found to be particularly toxic.

In the ointment preparation of the present invention, not only a good increase in the skin blood flow was observed in the skin blood flow test described below, but also a clear sustained effect was observed. This is because the prostacyclin, which is the main ingredient of the ointment preparation of the present invention, is rapidly and persistently absorbed from the skin site, and has a long-term therapeutic effect. This is the best.

[0067]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples. The present invention is not limited to this.

Example 1 9 (O) -methano-Δ ^{6 (9} α ⁾
-Prostaglandin I ₁ methyl ester 800 mg
Was dissolved in 100 g of diisopropyl adipate.
0.25 g of this solution was added to molten paraffin 10
g and white petrolatum Add to proper amount of mixture, total 100g
After adjusting to, the mixture was uniformly mixed and cooled to obtain an ointment.

Example 2 9 (O) -methano-Δ ^{6 (9} α ⁾
800 mg of prostaglandin I ₁ methyl ester were dissolved in 100 g of diisopropyl adipate. 0.25 g of this solution was added to 5 g of molten paraffin,
5 g of liquid paraffin and white petrolatum were added to an appropriate amount of the mixture to adjust the total amount to 100 g, and this was uniformly mixed and cooled to obtain an ointment.

Example 3 17 (S), 20-Dimethyl-9 (O) -methano-Δ ^{6 (9} α ⁾ -prostaglandin I
100 mg of _1- methyl ester was dissolved in 100 g of diisopropyl adipate. 0.25g of this solution
Was added to a mixture of 10 g of melted paraffin and an appropriate amount of white petrolatum to adjust the total amount to 100 g, and this was uniformly mixed and cooled to obtain an ointment.

Comparative Example 1 9 (O) -methano-Δ ^{6 (9} α ⁾
-Prostaglandin I ₁ methyl ester 800 mg
Was dissolved in 100 g of diisopropyl adipate.
0.25 g of this solution was added to molten liquid paraffin
4.5g and white petrolatum Add to the proper amount of mixture, the total amount 1
After adjusting to 00 g, this was uniformly mixed and cooled to obtain an ointment.

[Comparative Example 2] 9 (O) -methano-Δ ^{6 (9} α ⁾
40 mg of prostaglandin I ₁ methyl ester were dissolved in 100 g of diisopropyl adipate. 5 g of this solution was added to a mixture of 10 g of molten paraffin and an appropriate amount of white petrolatum to adjust the total amount to 100 g, and this was uniformly mixed and cooled to obtain an ointment.

[Comparative Example 3] 9 (O) -methano-Δ ^{6 (9} α ⁾
40 mg of prostaglandin I ₁ methyl ester were dissolved in 100 g of diisopropyl adipate. 5 g of this solution was added to 95 g of melted white petrolatum to adjust the total amount to 100 g, and this was uniformly mixed and cooled to obtain an ointment.

Comparative Example 4 17 (S), 20-Dimethyl-9 (O) -methano-Δ ^{6 (9} α ⁾ -prostaglandin I
100 mg of _1- methyl ester was dissolved in 100 g of diisopropyl adipate. 0.25g of this solution
Was added to a mixture of 4.5 g of melted liquid paraffin and an appropriate amount of white petrolatum, and the total amount was adjusted to 100 g.
This was mixed uniformly and cooled to obtain an ointment.

Comparative Example 5 17 (S), 20-Dimethyl-9 (O) -methano-Δ ^{6 (9} α ⁾ -prostaglandin I
₁ Methyl ester 5mg diisopropyl adipate
It was dissolved in 100 g. 5 g of this solution was added to a mixture of 10 g of molten paraffin and an appropriate amount of white petrolatum to adjust the total amount to 100 g, and this was uniformly mixed and cooled to obtain an ointment.

Comparative Example 6 17 (S), 20-Dimethyl-9 (O) -methano-Δ ^{6 (9} α ⁾ -prostaglandin I
₁ Methyl ester 5mg diisopropyl adipate
It was dissolved in 100 g. 5 g of this solution was added to 95 g of melted white petrolatum to adjust the total amount to 100 g, and this was uniformly mixed and cooled to obtain an ointment.

[Experimental Example 1] Test for releasing the active ingredient from the base A test for releasing the active ingredient from the base was carried out for the purpose of confirming that the ointment of the present invention regulates the release of the active ingredient. 70 mg of the ointments obtained in Examples and Comparative Examples were uniformly applied on a glass surface of 10 cm ² , and dipped in a 40% aqueous ethanol solution (reservoir solution). A part of this solution was sampled with time, and the main drug in the solution was quantified by liquid chromatography. The amount of the main drug released in the reservoir solution with respect to the amount of the main drug in the applied ointment was defined as the release rate (%). First result
Shown in the figure. The vertical axis represents the release rate, and the horizontal axis represents the time elapsed after the composition was applied. Release rate (%) = (amount of main drug in reservoir solution / amount of main drug in applied ointment) × 100 From the test results, the ointments of the examples of the present invention are the same ointment of higher paraffin hydrocarbon. The sustained release of the main drug was observed as compared with the comparative example, which is an agent.

[Experimental Example 2] Skin site blood flow test In order to confirm the local efficacy of the ointment of the present invention, the skin blood flow at the administration site was measured. The compositions obtained in Examples and Comparative Examples were non-sealed by 23 mg each on 1 cm × 1 cm of the thigh of hairless rats anesthetized with urethane.

After application, the skin blood flow at the administration site was measured with a laser Doppler blood flow meter. As a result, the difference before and after applying the ointment was obtained as the blood flow increase value. The results are shown in FIG. 2 and FIG.
Shown in. The vertical axis represents the difference in blood flow before and after application of the composition as a blood flow increase value, and the horizontal axis represents the time elapsed after application of the composition in time.

From the test results, it was confirmed that the ointment of the example of the present invention has a markedly prolonged blood flow increasing action as compared with the comparative example which is an ointment of the same higher paraffin hydrocarbon.

[0081]

The action and effect of the present invention, the ointment preparation of the present invention, sustained release from the ointment of the main drug is observed in the release test, not only a significant increase in skin blood flow is seen in the skin blood flow test, A clear persistence of medicinal effect was observed. This is sufficient support for the fact that the ointment preparation of the present invention is rapidly absorbed from the skin site, exerts a medicinal effect, and further has a medicinal effect lasting for several hours, which is unprecedented in terms of formulation. .

As described above, the ointment base of the present invention is highly active and has a short life in vivo, and the prostacyclins represented by the above formula [1] may become ulcerative skin diseases and ulcerative skin diseases. It is an excellent ointment formulation that has desirable effects when applied to the skin, that is, sustained drug efficacy, stability of the main drug, and low irritation to the skin site, ulcerative skin disease, Barja disease. It can be expected to be used as a therapeutic drug for peripheral circulatory failure.

[Brief description of drawings]

1 is an illustration of the results of a release test of the active ingredient from the formulation of the present invention.

FIG. 2 is an illustration of test results for skin blood flow in topical application of the preparation of the present invention.

FIG. 3 is an illustration of test results for skin blood flow in topical application of the preparation of the present invention.

Claims (3)

[Claims] 1. The following formula [1] as a medicinal component: [In the formula, R ¹ represents a hydrogen atom or a C _{1 to} C ₁₀ linear or branched alkyl group. R ² is R ²¹ or (CH ₂ ) _n
Represents R ²² , wherein R ²¹ is an optionally substituted C _3-
C _{12 represents} a linear or branched alkyl group, alkenyl group or alkynyl group, R ²² represents an optionally substituted C _{3 to} C ₁₀ cycloalkyl group, and n is 0 to 0.
Represents an integer of 2. R ³ and R ⁴ are each independently a hydrogen atom or a compound of the formula [2] -C (= O) R ⁵ --- [2] (wherein R ⁵ is a straight chain of C _{1 to} C ₅ Or a branched alkyl group))], a prostacyclin and / or an enantiomer thereof, a higher paraffin hydrocarbon as a base, and a fatty acid ester as a solubilizer. A composition for skin application containing a prostacyclin. 2. The prostacyclin-containing skin application composition according to claim 1, wherein the higher paraffinic hydrocarbon in the base is a mixture of paraffin and white petrolatum, and liquid paraffin is added if necessary. object. 3. The prostacyclin-containing skin application composition according to claim 1, wherein the fatty acid ester which is the solubilizer is diisopropyl adipate.